HIV is fueling a dramatic increase in the M. tuberculosis (MTB) epidemic particularly in sub-Saharan Africa, where in some countries up to 70% of tuberculosis (TB) patients are co-infected with HIV. Co-infection can accelerate the natural history of both diseases. In contrast to most other opportunistic infections associated with HIV, increased risk with M. tuberculosis begins within the first year after HIV infection. A better understanding of the basic immunology that allows HIV to dramatically increase the risk of TB is urgently needed to identify specific clinical and immunologic characteristics of co-infected individuals at greatest risk for developing active disease. Development of immunotherapy and therapeutic vaccines targeted to HIV/TB dually infected individuals would greatly benefit from an improved understanding of the immunological interface of TB and HIV. As access to treatment for HIV and TB increases in Africa, an understanding of the immunology of this potentially lethal co-infection is needed to allow optimal use of treatment resources. Containment of MTB is through cell-mediated immunity primarily involving CD4+ and CD8+ T cells and antigen presenting cells (APC) including both macrophages and dendritic cells (DC). HIV productively infects three of these cell types. This provides the setting and opportunity for significant cellular interactions between CD4+ T cells and APC during dual infection. Our overall hypothesis is that chronic immune activation and specific interactions between CD4+ T cells and APC in the setting of HIV/TB dual infection results in a loss of frequency and functionality of MTB-specific T cells thereby increasing the risk of reactivation or progressive primary TB. We will examine this hypothesis with the following aims: Aim 1. To determine the frequency and functional defects of MTB-specific CD4+ and CD8+ T cells and their relationship to chronic immune activation in HIV/TB dually infected individuals. The phenotype, frequency, and functionality of MTB-specific CD4+ and CD8+ T cells will be determined from a well clinically characterized set of Ugandan samples in their ability to make IFN-gamma, IL-2, TNF-alpha, MIP1-alpha, CD107a, and IL-17 in response to MTB. We have access to multiple cohorts of subjects in Uganda to study. Aim 2. To determine the specific cellular interactions of CD4+ cells, DC and macrophages that promote loss of control of MTB in dual infection using in vitro models. The effects of HIV/TB dual infection on the ability of macrophages and DC to transmit HIV to CD4+ T cells in the immunologic synapse will be determined. Aim 3. To determine the specific cellular interactions of CD4+ cells, DC and macrophages that promote loss of control of MTB in dual infection using tissue explant models. HIV and MTB replication will we examined in lymphoid tissues by live cell imaging microscopy using fluoro-labeled HIV and MTB. PUBLIC HEALTH RELEVANCE: This project will help understand how becoming HIV infected dramatically increases the risk of developing tuberculosis (TB) disease. Dual infection with TB and HIV is a very significant health problem particularly in Africa and Asia. This work could aid in the development of better vaccines and drugs to combat this co-infection.